Abstract Acute myocardial infarction (MI) is a major cause of morbidity and mortality in the US, within both the veteran and civilian populations. Proinflammatory cytokines are known to play a central role in post-MI tissue injury, remodeling and failure. Interleukin-18 (IL-18) is an inducible proinflammatory cytokine, and amplifies many autoimmune and inflammatory responses via the induction of other cytokines, chemokines, and adhesion molecules. Our studies, both published and preliminary, clearly indicate that IL-18 participates in pathological remodeling post-MI. Based on these findings, our central hypothesis is that IL-18 plays a pivotal role in myocardial remodeling post-MI by promoting cardiomyocyte apoptosis and hypertrophy, by regulating the deposition and composition of extracellular matrix, and by inducing fibroblast proliferation and fibrosis. While our long-term objective is to delineate the precise pathological role of proinflammatory cytokines in myocardial remodeling, our immediate goal is to establish an etiological role for IL-18 in post-MI cardiac remodeling and failure. To address our central hypothesis, three specific aims are proposed: In Specific Aim 1, we will define the causal role of IL-18 in vivo in post-infarct cardiac remodeling and failure using wild-type, cardiac-specific IL-18 knockout, and cardiac-restricted overexpressor (IL-18 transgenic) mice. In Specific Aim 2, we will characterize the effects of IL-18 on cell death and hypertrophy in cardiomyocytes in vitro. In Specific Aim 3, we will identify the IL-18-dependent molecular mechanisms responsible for migration and proliferation of cardiac fibroblast in vitro. These novel and innovative studies will integrate functional, molecular, biochemical and histological approaches in order to address the central hypothesis. Our proposed in vitro studies in cardiomyocytes and cardiac fibroblasts will help refine and further support our in vivo studies by delineating the molecular mechanisms that connect IL-18 signaling to this maladaptive phenotype. Completion of our proposed studies will provide a better understanding of the pathobiological processes involved in myocardial injury and remodeling post-MI, establish IL-18 as a causative factor, and thus identify it as a potential therapeutic target in post-MI cardiac injury and remodeling.